酰卤是一种强酰化剂，可以和醇或胺迅速反应生成酯或酰胺。酰卤易水解，一般情况下，反应体系需要保证无水。但是在水溶液中酰卤也是可以用于合成酯或酰胺的，这个反应就是Schotten-Baumann反应。

反应机理

在没有碱的时候，氢离子抑制反应平衡，酰胺化不能进行完全：

反应特点：

1、胺的酰基化必须要加碱，因为生成的副产物酸可以对底物胺进行质子化，使其活性降低（碱的碱性必须比胺强）。

2、伯醇酰基化时，有时可以不加碱。但仲醇和叔醇酰基化时必须要加碱。

3、醇的反应活性顺序：1°>2°>3°，所以大位阻的仲醇或叔醇反应很慢。

4、胺的反应顺序和胺的亲核性有关，亲核性越强反应越快。

5、酰卤的活性对于反应的成功与否也至关重要，通常活性越低的酰卤反应产率越高（因为低活性的酰卤水解较慢）。

对于大位阻的底物的酰基化反应可以在有机碱（e.g., pyridine,DMAP, etc.）或路易斯酸催化下在强极性非质子溶剂中进行，这些反应也可以看作是最原始的Schotten-Baumann反应的改进法。

PS: 其实反应利用的还是胺、醇和水的亲核性不同，以及酰氯与水反应速率和酰氯与胺或醇的反应速率差异来进行的。所以：

1. 如果水的亲核性比醇或胺更高，反应是不是应该醇或胺先和碱加到水中（或其他溶剂的混合溶液），再滴加酰氯？
   

2. 如果酰氯的活性比较低，是不是可以醇或胺先和酰氯溶在水中（或其他溶剂的混合溶液），再滴加碱？

3. 对酰氯和醇或胺的活性不好把握时，是不是采取最终滴酰氯的方法更合适？

4. 既然有的反应要加其他溶剂，为什么一定要加水？加水可以增加无机碱溶解度，避免非均相反应中无机碱颗粒度、搅拌等带来的影响。

应用案例

【J. Med. Chem. 2000, 43, 4189-4199】

【Org. Lett., 2002, 4, 4717-4718.】

Org. Synth. 2019, 96, 528

详细操作：

A 1-L three-necked, round-bottomed flask (24/40) is equipped with a Teflon-coated, oval, magnetic stir bar (2 cm x 2 cm x 4 cm) and L-phenylalanine methyl ester hydrochloride (1) (21.6 g, 0.1 mol, 1.0 equiv) , a saturated aqueous solution of NaHCO3(500 mL), and DCM (300 mL)  are added under an air atmosphere.

Magnetic stirring is commenced (Evolution of CO2 is observed from the neutralization of the HCl salt of the starting material 1) and the reaction mixture is allowed to stir for 20 min (CO2 evolution ceased due to full neutralization. The pH of the aqueous layer was ≈ 8), at which point, methyl malonyl chloride (15.1 g, 11.8 mL, 0.11 mol, 1.1 equiv)  is added drop-wise via syringe (The neat chloride solution was added dropwise, by hand, at a rate of ≈ 1 mL/min over a period of ≈ 12 minutes. Avoid contact of the reagent with adventitious moisture.) through the septum fitted on the central neck of the reaction flask.

After completion of the addition of methyl malonyl chloride, the reaction mixture is allowed to stir for 20 min (Evolution of CO2 had ceased and the reaction was deemed complete. The pH of the aqueous layer was ≈ 8.). The reaction mixture is then transferred  to a 1-L separatory funnel, and the two phases are allowed to settle, the organic layer is removed.

The remaining aqueous layer in the separatory funnel is extracted with DCM (2 x 150 mL). The organic layers are combined into a 1-L Erlenmeyer flask, dried over anhydrous Na2SO4 (~ 20 g)  and filtered into a tared 1-L one-necked, round-bottomed flask. The bulk of the solvent is removed on a rotary evaporator. Residual solvent is removed by placing the flask under high vacuum with agitation at 45 °C, which affords the product (2) 27.8 g, 99% as a faint yellow oil . 

OPRD（dx.doi.org/10.1021/op300185s |）中两个不加水的案例，大家想想，乙酰氯关环是怎么进行的，反应能不能加水？